1,5-diazabicyclo-(3.3.0)-octanes



United States Patent 3,449,359 1,S-DIAZABICYCLO-[3.3.0]-0CTANES EmilioTesta, Tessin, Switzerland, Elvio Bellasio, Como, and Giulio Malfii,Milan, Italy, assignors to Lepetit S.p.A., Milan, Italy No Drawing.Filed Feb. 7, 1966, Ser. No. 525,364 Claims priority, application GreatBritain, Feb. 9, 1965, 5,610/65 Int. Cl. C07d 49/44, 53/00; A61k 27/00US. Cl. 260-310 7 Claims ABSTRACT OF THE DISCLOSURE New 1,5diazabicyclo-[3,3,0]-octane-2,6-diodes, prepared from abeta-bromo-propionyl chloride and hydrazine or a 3-pyrazolidinone, andthe hydrogenation products of such diones. The compounds possessanti-inflammatory activity.

This application is concerned with 1,5-diazabicyclo-[3,3,0]-octane-2,6-diones and their derivatives. More particularly, thecompounds of the invention are represented by the formula:

wherein R, R R and alkyl or phenyl.

The process for preparing the new class of compounds which form thesubject of this invention consists in refluxing a beta-bromopropionylchloride having the formula:

R each represent hydrogen, lower R1/ CHzBr I with an equimolecularamount of a 3-pyrazolidinone having the formula:

HN--C O R wherein R and R still have the above significance. Thesymmetrical hydrazine is then converted to the octanedione either bysimple distillation, or by refluxing in an inert anhydrous organicsolvent in the presence of two equimolecular amounts of tertiary organicbase.

The l,5-diazabicyclo[3.3.0]-octanes of the invention possess a highdegree of anti-inflammatory activity.

Moreover, they may be converted, if desired, into the corresponding1,5-diazabicyclo[3.3.0]octanes having the formula:

wherein R, R R and R still have the above significance, by hydrogenationwith LiAlH in a solvent. The hydrogenated derivatives have alsodesirable pharmacological properties; for example, a derivative of thisclass, i.e., 3,3,7,7-tetramethyl-l,5-diazabicyclo[3.3.0] octane, whenadministered by oral route to rats has shown an average percentagedecrease of granuloma of 13.5 in the granuloma pellet test.

The anti-inflammatory activity of the new1,5-diazabicyclo[3.3.0]-octane-2,6-diones is shown by the followingtable, setting out some members of the group in comparison with the wellknown agent phenylbutazone. The socalled granuloma pellet test wascarried out to evaluate the inhibitory activity on the connectivalproliferation induced by an inflammatory stimulants. The products wereadministered by oral route at a does of -mg./kg. to adrenectomised rats.The intraperitoneal LD is also given. Reference is made to the genericformula for the significance of the symbols R.

TABLE Percent decrease of R R2 R LD granuloma n-C4H n-C4H I1-C4Hp 1, 0007. 5 11-04110 CH CH 300 -8. 6 Il-CrHn C2115 02115 500 9. 3 l'l-C4H9II'C3H7 11C3H7 1, 000 10. 5 11-04119 CsHa H l, 000 10. 2 Il-C H9 C5115C5H5 1, 000 --ll. 1 H C2115 02135 1, 000 -7. 8 Phenylbutazone 205 -7. 4

The following examples are illustrative of the products and processes ofthe present invention.

EXAMPLE 1 3,3,7,7-tetramethyl-1,5-diazabicyclo[3.3.0]octane-2,6-

To a solution of 13.3 g. of 4,4-dimethyl-3-pyrazolidinone in 300 ml. ofanhydrous benzene a solution of 23.2 g. ofalpha-alpha-dimethyl-beta-bromopropionyl chloride in 30 ml. of anhydrousbenzene is cautiously added, followed by a solution of 29.4 g. oftriethylamine in 40 ml. of benzene. After heating for 8 hours to reflux,the mixture is cooled, filtered and the filtrate evaporated to drynessin vacuo. The residue is recrystallised from petroleum ether-isopropylether mixture. Yield 15 g. (66%). The compound has M.P. 158-160 C.

EXAMPLE 2 3-phenyl-7,7-dibutyl 1,5 diazabicyclo[3.3.0]octane-2,6-

dione To a solution of 13.5 g. of 4,4-dibutyl-3-pyrazolidinone in ml. ofbenzene a soltuion of 16.88 g. of alphaphenyl-beta-bromopropionylchloride in 50 ml. of benzene is added gradually, followed by 17.2 g. oftriethylamine in 50 ml. of benzene. After heating to reflux for 9 hoursthe mixture is worked up as in the preceding example. The residue frombenzene is distilled collecting at ZOO-202 C./0.5 mm. Yield 15.7 g.(70%).

3 EXAMPLES 3 TO 13 By a process analogous to that set out in Examples 1and 2 the following 1,5-diazabicyclo[3.3.0]octane-2,6-diones wereprepared, of which the yield and properties are given (reference is madeto the generic formula for the significance of the symbols R).

Into a solution of 19 g. of alpha, alpha-dipropyl-betabromopropionylchloride in 100 ml. of benzene, 2.39 g. of hydrazine hydrate are slowlyadded with external cooling. The mixture is then heated at 60 C. for 2hours, cooled and diluted with 100 ml. of benzene and 50 ml. of water.The benzene layer is separated and concentrated to a small volume, thenan equal volume of petroleum ether is added. The white precipitate isN,N-di-(alpha,alphadipropyl-beta-bromo-propionyl) hydrazine, M.P. 164-168 C. Yield 12.5 g. (75% A mixture of 7.6 g. of this hydrazine, 8.27 g.of triethylamine and 400 ml. of henzene is refluxed for 2 hours. Aftercooling and filtration, the solvent is distilled off giving 2.3 g.(yield 46%) of 3,3,7,7-tetrapropyl-1,5-diazabicyclo-[3.3.0] octane 2,6-dione, M.P. 70 71 C (from petroleum ether).

EXAMPLE 15 '3,3,7,7-tetrabutyl 1,5 diazabicyclo[3.3.0]octane 2,6- dioneEquimo'lecular amounts of alpha, alpha-dibutyl-betabromopropionylchloride and hydrazine hydrate are reacted under the conditionsdescribed in Example 14. The residue from benzene is distilled and goesover at 190 C./ 1 mm. Yield 36% of3,3,7,7-tetra-butyl-1,5-diazabicyclo[3.=3.0]octane-2,6-dione.

EXAMPLE 16 3,3,7,7-tetramethyl-l,54iiazahicyclo[3.3.0]octane To anamount of 8.34 g. of LiAlH in 160 ml. of tetrahydrofuran, 10.8 g. of3,3,7,7-'tetramethyl-1,5-diazabicyclo [3.3.0]-octane-3,6-dione dissolvedin 100 ml. of the same solvent are slowly added at C. and understirring. The mixture is refluxed for 6 hours, then another amount of4.5 g. of LiAll-I; (4.5 g.) is added and the mixture is again refluxedfor 5 hours. Water is then added at 0 C. under stirring. The mixture isfiltered and the filtrate is concentrated in vacuo, the residue is takenup with diethyl ether, the mixture is filtered and the filtrate isconcentrated in vacuo. The oily liquid so obtained is distilled, thusyielding 5 g. (62.5%) of 3,3,7,7-tetramethyl-l,5- diazabicyclo 3 3.0]octane.

What we claim is:

1. A compound of the formula wherein R, R R and R are each a member ofthe class consisting of hydrogen, lower alkyl, and phenyl.

2. 6,3 di n butyl 7,7-di-n-propyl-1,5-diazabicyclo[3.3.0]=octane-2,6-dione. v

'3. 3,3 di n butyl 7 phenyl-1,5-diazabicyclo [3.3.0]octane-2,6-dione.

4. 3,3 di n buty1-7,7-diphenyl-1,5-di-azabicyclo [*3.3.0]octane-2,6dione.

5. 7,7 diethyl-LS-diazabicyclo[3.3.0]octane-2,6-dione.

6. 3,3,7,7 tetramethyl-l,5-diazabicyclo[3.3.0]octane.

7. A compound of the formula wherein one of the groups, R, R R and R isa member of the class consisting of hydrogen, lower alkyl and phenyl,while the others are each a member of the class consisting of loweralkyl and phenyl.

References Cited UNITED STATES PATENTS 4/.l957' Wagner et al. 4/ 1958Hafiiger et al.

OTHER REFERENCES HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

US. Cl. X.R.

